Recent studies in our laboratory have shown that distinct forms of glutamate dehydrogenase are present in mammalian brain and that abnormalities of this enzyme occur in neural and extraneural tissues of patients with late onset neuro- degenerative disorders. The long-term objects of this proposal are twofold: The first is to further characterize the different GDH components and determine as to whether they represent genetically determined variants or products of post-translational modification. The second is to define the precise molecular defect(s) that are responsible for the altered enzyme activity found in the neurological patients. We propose: 1) to study further the kinetic and electrophoretic characteristics of the purified GDH forms from extraneural and neural tissues of patients and controls. 2) To search for differences in the primary structure of the enzyme in health and disease. 3) To study the synthesis of GDH by cultured skin fibroblasts of patients and controls and investigate whether post- translational modification(s) of the enzyme molecule occurs in human tissues, and if so as to whether this is altered in the disease state. 4) To determine the subcellular localization of the enzyme in brain in order to better understand its role in nervous system function and dysfunction. These studies are expected to lay the groundwork for cloning the human GDH gene(s) and exploring its possible polymorphism in human degeneratives disorders.